Joke Lenoir

Partial hydrolysis of poly(2-ethyl-2-oxazoline) and potential implications for biomedical applications?

The hydrolysis of PEtOx is studied to evaluate the potential toxicity of partially hydrolyzed polymers that might interfere with its increasing popularity for biomedical applications. The hydrolysis of PEtOx is studied in the presence of digestive enzymes (gastric and intestinal) and at 5.8 M hydrochloric acid as a function of temperature (57, 73, 90, and 100 °C). It is found that PEtOx undergoes negligible hydrolysis at 37 °C and that thermal and solution properties are not altered when up to 10% of the polymer backbone is hydrolyzed. Mucosal irritation and cytotoxicity is also absent up to 10% hydrolysis levels. In conclusion, PEtOx will not decompose at physiological conditions, and partial hydrolysis will not limit its biomedical applications.

Mucosal irritation potential of polyelectrolyte multilayer capsules

Polyelectrolyte multilayer capsules have recently gained interest as carriers for drug delivery. When envisioning mucosal administration, one is focused with potential concerns such as tissue irritation and tissue damage, induced by the carrier itself. In this paper we demonstrate the use of a slug-based (Arion lusitanicus) assay to evaluate the mucosal irritation potential of different types of polyelectrolytes, their complexes and multilayer capsules. This assay allows to assess in a simple yet efficient way mucosal tissue irritation without using large numbers of vertebrates such as mice, rabbits or non-human primates. We found that although single polyelectrolyte components do induce tissue irritation, this response is dramatically reduced upon complexation with an oppositely charged polyelectrolyte, rendering fairly inert polyelectrolyte complexes. These findings put polyelectrolyte multilayer capsules further en route towards drug delivery applications.

Dressings Loaded with Cyclodextrin–Hamamelitannin Complexes Increase Staphylococcus aureus Susceptibility Toward Antibiotics Both in Single as well as in Mixed Biofilm Communities

Bacteria reside within biofilms at the infection site, making them extremely difficult to eradicate with conventional wound care products. Bacteria use quorum sensing (QS) systems to regulate biofilm formation, and QS inhibitors (QSIs) have been proposed as promising antibiofilm agents. Despite this, few antimicrobial therapies that interfere with QS exist. Nontoxic hydroxypropyl-β-cyclodextrin-functionalized cellulose gauzes releasing a burst of the antibiotic vancomycin and the QSI hamamelitannin are developed, followed by a sustained release of both. The gauzes affect QS and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of chronic wound infection and can be considered as candidates to be used to prevent wound infection as well as treat infected wounds.

Influence of reaction medium during synthesis of Gantrez AN 119 nanoparticles for oral vaccination.

Two synthesis methods of poly(methyl vinyl ether-co-maleic anhydride) (Gantrez AN 119) nanoparticles (NP) (used for oral vaccination) were compared. Wheat germ agglutinin (WGA) was used as ligand to enhance the bioadhesive properties of NP and beta-galactosidase as antigen. The first method encapsulated beta-galactosidase in NP by co-precipitation in an acetone/water mixture containing 44% acetone. In the second method, antigen addition occurred in 100% acetone. To improve stability, NP were crosslinked with 1,3-diaminopropane. The stability of WGA-conjugated NP with encapsulated antigen diminished at lower pH and when decreasing the amount of crosslinker. The binding type between WGA and polymer depended on the synthesis method: predominantly ionic bonds were formed using the 44% acetone method, whereas synthesis via the 100% acetone method resulted in covalent bonds. The biological activity of the WGA coating, evaluated via a pig gastric mucin binding test, was lower in NP prepared via the 100% acetone method. No release of native antigen was detected after hydrolysis of NP, due to the covalent antigen binding during antigen encapsulation and the high reactivity of the polymer. Moreover, the mucosal irritation capacity was evaluated upon nanoparticle hydrolysis using a slug mucosal irritation assay. Herein, hydrolysed NP of the 44% acetone method were classified as mild irritative.

The slug mucosal irritation (SMI) assay: development of a screening tool for the evaluation of ocular discomfort caused by shampoos.

In this research, the slug mucosal irritation (SMI) assay was applied to predict ocular discomfort caused by shampoos to investigate the correlation between responses in slugs and humans. Several SMI experiments and a human eye irritation test (HEIT) were performed with 1 artificial tear solution (ArtTear) and 5 shampoos (A-E; 5%-dilution). In the HEIT, evaluation was performed by participants and an ophthalmologist at several time points. Analyses reveal that (1) a significant positive association existed between immediate stinging reaction reported by the participants and the mean total mucus produced by the slugs (MTMP) (Spearmans Rank correlation=0.986, p<0.001); (2) ArtTear was best tolerated in both tests; (3) moreover, all shampoos induced higher reactions than ArtTear and water; (4) Shampoo A induced the highest MTMP and received higher scores for immediate discomfort; (5) B was the best tolerated shampoo in both tests, while C, D and E resulted in more pronounced reactions; (6) lacrimation was found not to be statistically correlated with discomfort sensations reported by the participants. The SMI assay is a promising evaluation method for discomfort in the human eye. Screening prototype (eye) formulations with this assay allows formula optimization prior to a HEIT.

New aspects of the Slug Mucosal Irritation assay: predicting nasal stinging, itching and burning sensations

Stinging, itching and/or burning (SIB) sensations cannot be detected by animal tests or in vitro models. In the past, the Slug Mucosal Irritation (SMI) assay demonstrated a relation between an increased mucus production in slugs and an elevated incidence of SIB sensations in humans. A new 1‐day SMI test procedure was developed focusing on the prediction of these short‐term sensations. The objective of this study was to verify whether this new procedure is capable predicting mucosal tolerance of several marketed nasal formulations using the slug Arion lusitanicus. Irritation and tissue damage were quantified with a 5‐day repeated exposure study by means of the mucus produced and proteins and enzymes released. The new protocol predicted SIB sensations by means of mucus production. The effects of six liquid nasal formulations were tested with both protocols, while five physiologic saline solutions were only tested with the new protocol to optimize it. None of the tested liquid nasal formulations resulted in tissue damage; however, exposure to the different formulations had a clear effect on the mucus production of the slugs and moderate discomfort was observed in some cases. These effects were due to the active ingredient, the presence of benzalkonium chloride as a preservative or the hyperosmolality of the formulation. For the most part results agreed with clinical data found in literature. It was concluded that the SMI assay, and the new 1‐day protocol in particular, is a good tool to predict nasal clinical discomfort. Copyright

The Slug Mucosal Irritation (SMI) assay: a tool for the evaluation of nasal discomfort.

In this research project, the Slug Mucosal Irritation (SMI) assay was applied to predict nasal discomfort, investigating the correlation between responses in slugs and humans. Several SMI experiments and a Human Nose Irritation Test (HNIT) were performed with five NaCl solutions (0.4%, 1.3%, 2.6%, 5.4% and 10.4%) and two benzalkonium chloride solutions (BAC 0.02% and BAC 0.05%). In the HNIT, subjective evaluation of clinical discomfort was performed by 24 participants at several time points. Analyzes reveal that (1) a significant positive association existed between immediate stinging reaction reported by the participants and the mean total mucus production of the slugs (Spearmans Rank correlation=0.963, p<0.001); (2) NaCl 0.4% was best tolerated in both tests; (3) a concentration-response effect was observed for NaCl and BAC solutions; (4) NaCl 10.4% induced the highest mucus production in the slugs and received higher sting scores for immediate discomfort in the HNIT; (5) stinging sensations decreased rapidly in time and (6) based on these results a new classification prediction model for nasal applications was established. In conclusion, the SMI assay is a promising evaluation method for clinical nasal discomfort. Screening (prototype) formulations with this assay allows formula optimization prior to a clinical trial.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System

PurposeNeonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage formMethodsZinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potencyResultsPresently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends.ConclusionThese promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.